The radioprotective effects of inflammatory cytokines such as IL 1 and TNF are based on the induction of hematopoietic cytokines and regulation of the expression of functional cytokine receptors e.g., IL 1 upregulates not only the production of G-CSF and GM-CSF, but also the expression of receptors for IL 1 by ten-fold as well as receptors for G- CSF and GM-CSF on bone marrow cells (BMC). The mechanism of radioprotection may involve the induction of scavengers of oxygen radicals. Both IL 1 and TNF are potent inducers of mitochondrial MnSOD. Cells transfected with the cDNA for this free radical scavenger become more radioresistant, and also more resistant to agents that generate oxygen radicals such as adriamycin, mitomycin C, as well as to TNF and IL 1 themselves. Thus, induction of MnSOD may contribute to the radioprotective effects of cytokines. Based on the premise that injury to DNA may be a fundamental cause of mutagenesis, we are also investigating the effect of cytokines on carcinogenesis. JB6, an immortalized but nontumorigenic murine epidermal cell line, when incubated with PMA lose their anchorage dependence, as indicated by increased colony formation in soft agar, and become tumorigenic in nude mice. This is inhibited by the addition of anti-promoters, such as retinoids. Of the cytokines with differentiation activities, including IFNalpha, IL 6, IL 1, and TGFbeta tested, only TGFbeta synergized with retinoic acid in a dose-dependent manner in reducing the number of JB6 colonies induced by PMA. Conversely, TNF` had the opposite effect, and like PMA, promoted colony formation by both JF6 and 3T3 cells. Thus cytokines may influence tumorigenic cells by countering or promoting their neoplastic transformation and/or growth.